Transient receptor potential-melastatin 4 (TRPM4) is a Ca2+-activated, but Ca2+-impermeable, cation channel. Increasing [Ca2+](i), induce current activation and reduction through TRPM4 channels Several TRPM4 isoforms are expressed in mice and humans. but rat TRPM4 (rTRPM4) has not been previously identified Here, we identified, cloned, and characterized two rTRPM4 isoforms, rTRPM4a and rTRPM4b, using 5'-RACE-PCR rTRPM4b channel activity increased with [Ca2-], in a dose-dependent manner. However, the rTRPM4b Ca2+-dependent activity at negative potentials differed from that of human TRPM4b (hTRPM4b), even though both represent full-length proteins. Additionally. rTRPM4b showed a slightly different single-channel current amplitude and open time distribution than hTRPM4b However, rTRPM4a, which lacks the N-terminal region of rTRPM4b, and hTRPM4a had no similar functional channel activities. Furthermore, we characterized splicing regions. tissue distribution, and cellular localization of these isoforms. Unlike rTRPM4a. rTRPM4b was localized to the membrane at high levels. suggesting that rTRPM4b is the functionally active channel. Crown Copyright (C) 2009 Published by Elsevier Inc All rights reserved.